High Throughput Screening of Medicines for Malaria Ventures Chemical Libraries to Identify Novel Inhibitors of Candida auris

疟疾药物的高通量筛选帮助化学库鉴定新型耳念珠菌抑制剂

• 批准号: 10383652
• 负责人: Jose L. Lopez-Ribot
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383652
• 关键词: Academia; Amphotericin B; Antibiotic Resistance; Antifungal Agents; Antifungal Therapy; Awareness; Azoles; Biological; Biological Assay; Candida; Candida albicans; Candida auris; Candidiasis; Cell Line; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Clinic; Clinical; Collection; Data; Development; Disease; Disease Outbreaks; Dose; Epidemic; Etiology; Eukaryota; Fluconazole; Fluconazole resistance; Fungal Drug Resistance; Generations; Growth; Health care facility; Human; Immune; In Vitro; Infection; Laboratories; Libraries; Malaria; Medical; Medical Research; Medicine; Micafungin; Modeling; Modern Medicine; Molds; Multi-Drug Resistance; Mycoses; National Institute of Allergy and Infectious Disease; Nature; Nonprofit Organizations; Nosocomial Infections; Nursing Homes; Parasitology; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Polyenes; Primary carcinoma of the liver cells; Property; Resistance; Resistance development; Safety; Strategic Planning; Structure; Toxic effect; United States National Institutes of Health; Yeasts; base; combat; design; drug development; emerging pathogen; experimental study; fungus; health care settings; high throughput screening; in vitro activity; in vitro testing; inhibitor; interest; mortality; neglect; novel; novel strategies; novel therapeutics; pathogen; programs; public-private partnership; response; small molecule; small molecule libraries; trend

Candida species represent the most frequent etiological agents of opportunistic fungal invasive infections in an expanding spectrum of immune- and medically-compromised patients, and candidiasis now represents the third-to-fourth most frequent nosocomial infection worldwide, carrying unacceptably high mortality rates of 30-60%, which alarmingly have remained unchanged during the last three decades. Most recently, Candida auris has emerged as a multi-drug resistant opportunistic fungus around the globe, including the U.S, with a notable ability to easily spread between hospitalized patients and nursing home residents leading to major outbreaks in healthcare settings. According to data from the Centers for Disease Control and Prevention (CDC), 90% of C. auris strains in the U.S. have been resistant to fluconazole, 30% have been resistant to amphotericin B, and 5% have been resistant to echinocandins. Thus, the fact that some strains of C. auris demonstrate pan-resistance to all three major classes of clinically-used antifungals agents is particularly concerning. Indeed, in its recently released Antibiotic Resistance Threats in the United States, the CDC has designated C. auris as one of only 5 “Urgent Threats” requiring swift and aggressive action, since there is a grave concern that multi- and pan-resistant C. auris isolates will spread and become prevalent, and mostly untreatable, in the years to come. Thus, there is dire need for the development of novel therapeutics against this emerging pathogen. To conquer this formidable challenge, we propose a highly efficient approach by establishing a novel partnership between academia (our laboratory) and a non-for profit organization (Medicines for Malaria Ventures, MMV) in order to perform high throughput screening (HTS) of MMV’s chemical libraries containing 180,000 small molecule compounds to identify high value compounds with novel antifungal activity against C. auris. Although similar approaches have had a major impact in the Parasitology field, these MMV’s libraries have never before been screened for antifungal activity. To this end, we proposed the following: i) perform HTS of MMV’s chemical libraries to identify high value compounds with novel antifungal activity against C. auris, for which we will use a 384-well microtiter plate based model recently developed in our laboratory to screen MMV’s “Hit-Generation” (140K compounds) and “Diversity” (40K compounds) chemical libraries in order to identify inhibitors of C. auris growth; and ii) to characterize the leading compounds by performing a battery of in vitro tests to further establish their antifungal activity and safety/toxicity properties.

念珠菌属是机会性真菌入侵最常见的病原体 越来越多的免疫和医疗受损患者的感染，以及现在的念珠菌病 代表全球第三至第四最常见的医院感染，其携带率高得令人难以接受 死亡率高达 30-60%，令人震惊的是，这一数字在过去三十年中一直保持不变。最多 最近，耳念珠菌已成为全球范围内的一种多重耐药机会性真菌，包括 美国，具有在住院患者和疗养院居民之间轻松传播的显着能力 导致医疗机构发生重大疫情。根据美国疾病控制和预防中心的数据 预防 (CDC)，美国 90% 的耳念珠菌菌株对氟康唑具有耐药性，30% 已对氟康唑产生耐药性 对两性霉素B耐药，5%对棘白菌素耐药。因此，事实上，某些菌株 耳念珠菌表现出对临床使用的所有三大类抗真菌药物的泛耐药性 特别令人担忧。事实上，在美国最近发布的《抗生素耐药性威胁》中， CDC 已将耳念珠菌列为仅有的 5 个需要迅速采取积极行动的“紧急威胁”之一，因为 人们严重担心多重耐药和泛耐药的耳念珠菌分离株将会传播并流行，并且 在未来的几年里，大部分都是无法治愈的。因此，迫切需要开发新的治疗方法 对抗这种新出现的病原体。为了克服这一艰巨的挑战，我们提出了一种高效的方法 通过在学术界（我们的实验室）和非营利组织之间建立新型合作伙伴关系 （疟疾药物风险投资公司 (Medicines for Malaria Ventures)，MMV），以便对 MMV 进行高通量筛选 (HTS) 包含 180,000 个小分子化合物的化学库，可通过新颖的方法识别高价值化合物 针对耳念珠菌的抗真菌活性。尽管类似的方法对寄生虫学产生了重大影响 在该领域，这些 MMV 文库以前从未经过抗真菌活性筛选。为此，我们提出 以下内容：i) 对 MMV 的化学库进行 HTS，以识别具有新颖性的高价值化合物 针对耳念珠菌的抗真菌活性，我们最近将使用基于 384 孔微量滴定板的模型 我们实验室开发的用于筛选 MMV 的“热门生成”（140K 化合物）和“多样性”（40K 化合物）化学库，以鉴定耳念珠菌生长的抑制剂； ii) 表征 通过进行一系列体外测试来进一步确定其抗真菌活性，并 安全/毒性特性。

项目成果

High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms.

• DOI: 10.3390/jof9090879
• 发表时间: 2023-08-27
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Ajetunmobi OH;Wall G;Vidal Bonifacio B;Martinez Delgado LA;Chaturvedi AK;Najvar LK;Wormley FL Jr;Patterson HP;Wiederhold NP;Patterson TF;Lopez-Ribot JL
• 通讯作者: Lopez-Ribot JL